Following transplantation, recipient T cells can recognize and respond to donor antigens expressed directly on donor cells, and can respond to donor-derived peptides that have been processed and presented in the context of recipient MHC through the indirect pathway. Indirectly primed CD4+ T cells have been well studied in transplantation, but little information is available regarding whether indirectly primed CD8+ T cells participate in rejection. To address this, we placed MHC class I-deficient DbKb knockout skin grafts onto allogeneic H-2 k SCID recipients followed by adoptive transfer of purified H-2 k CD8+ T cells. The MHC class I-deficient grafts were rejected and only CD8+ T cells were detectable in the recipient lymphoid organs and in the skin grafts. Immunohistochemical analysis showed that CD8+ T cells were found in close proximity to vascular endothelial cells and to recipient infiltrating macrophages, suggesting specific interactions. The data demonstrate that cross-primed polyclonal CD8+ T cells can function as active participants in the effector phase of rejection. The findings confirm and extend previous studies using a monoclonal TCR transgenic T cell and shed light on mechanisms of acute and chronic graft injury that are potentially relevant to human transplant recipients.